Neuroprotection and mechanisms of atractylenolide III in preventing learning and memory impairment induced by chronic high-dose homocysteine administration in rats

Lee

et al. 2016

Sci Rep

We investigated the anti-amnesic effects of SJ and fermented SJ (FSJ) on scopolamine (SCO)-induced amnesia mouse model. Mice were orally co-treated with SJ or FSJ (125, 250, and 500 mg/kg) and SCO (1 mg/kg), which was injected intraperitoneally for 14 days. SCO decreased the step-through latency and prolonged latency time to find the hidden platform in the passive avoidance test and Morris water maze test, respectively, and both SCO effects were ameliorated by FSJ treatment. FSJ was discovered to promote hippocampal neurogenesis during SCO treatment by increasing proliferation and survival of BrdU-positive cells, immature/mature neurons. In the hippocampus of SCO, oxidative stress and the activity of acetylcholinesterase were elevated, whereas the levels of acetylcholine and choline acetyltransferase were diminished; however, all of these alterations were attenuated by FSJ-treatment. The alterations in brain-derived neurotrophic factor, phosphorylated cAMP response element-binding protein, and phosphorylated Akt that occurred following SCO treatment were protected by FSJ administration. Therefore, our findings are the first to suggest that FSJ may be a promising therapeutic drug for the treatment of amnesia and aging-related or neurodegenerative disease-related memory impairment. Furthermore, the molecular mechanism by which FSJ exerts its effects may involve modulation of the cholinergic system and BDNF/CREB/Akt pathway.

Section: Discussionmentioning

confidence: 99%

Fermented Sipjeondaebo-tang Alleviates Memory Deficits and Loss of Hippocampal Neurogenesis in Scopolamine-induced Amnesia in Mice

Lee

et al. 2016

Sci Rep

“…Atractylenolide I has been demonstrated to exhibit antitumour and anti-inflammation activities (Liu et al, 2013;Huang et al, 2014;Wang et al, 2009). Atractylenolide III has also been reported to exert anti-tumour activity (Kang et al, 2011), gastroprotective activity (Wang et al, 2010), and neuroprotection activities (Zhao et al, 2015). Therefore, atractylenolide I and III have been widely accepted as the excellent drug candidates.…”

Section: Introductionmentioning

confidence: 99%

Strong Specific Inhibition of UDP-glucuronosyltransferase 2B7 by Atractylenolide I and III

et al. 2015

Drug-metabolizing enzymes inhibition-based drug-drug interaction remains to be the key limiting factor for the research and development of efficient herbal components to become clinical drugs. The present study aims to determine the inhibition of uridine 5'-diphospho-glucuronosyltransferases (UGTs) isoforms by two important efficient herbal ingredients isolated from Atractylodes macrocephala Koidz, atractylenolide I and III. In vitro recombinant UGTs-catalysed glucuronidation of 4-methylumbelliferone was used to determine the inhibition capability and kinetics of atractylenolide I and III towards UGT2B7, and in silico docking method was employed to explain the possible mechanism. Atractylenolide I and III exhibited specific inhibition towards UGT2B7, with negligible influence towards other UGT isoforms. Atractylenolide I exerted stronger inhibition potential than atractylenolide III towards UGT2B7, which is attributed to the different hydrogen bonds and hydrophobic interactions. Inhibition kinetic analysis was performed for the inhibition of atractylenolide I towards UGT2B7. Inhibition kinetic determination showed that atractylenolide I competitively inhibited UGT2B7, and inhibition kinetic parameter (Ki) was calculated to be 6.4 μM. In combination of the maximum plasma concentration of atractylenolide I after oral administration of 50 mg/kg atractylenolide I, the area under the plasma concentration-time curve ration AUCi /AUC was calculated to be 1.17, indicating the highly possible drug-drug interaction between atractylenolide I and drugs mainly undergoing UGT2B7-catalysed metabolism.

“…Clinical investigations have shown that Hcy plasma levels are significantly higher in patients with neurologic disorders [41,42], being a strong independent risk factor for multiple sclerosis [43], Alzheimer's disease [44][45][46][47][48], and Parkinson's disease [46,49,50]. Additionally, a tight correlation has been reported between the elevated Hcy plasma levels and cognitive impairment in the elderly [41,51,52]. Accumulated evidences show that Hcy is a potent neurotoxin, which contributes to oxidative stress in the brain [48], where it binds and activates N-methyl-d-aspartate (NMDA) receptors [53,54], and mobilizes intracellular calcium stores [55] Figures 1 and 3) and, consequently, rescuing the decreased percentage of global DNA methylation due to BM to normal levels (Figure 4).…”

Section: Discussionmentioning

confidence: 99%

“…leading to caspase activation, DNA damage, and neuronal apoptosis in vitro[51,56,57] and in vivo[52,58,59]. Indeed, it has been reported that Hcy can upregulate Casp3 and activate caspase 3 via p38-mitogen-activated protein kinase (p38-MAPK)[60].…”

mentioning

confidence: 99%

Vitamin B₁₂is neuroprotective in experimental pneumococcal meningitis through modulation of hippocampal DNA methylation

Queiroz

Cavalcante-Silva

Lopes³

et al. 2020

Preprint

AbstractBackgroundBacterial meningitis (BM) causes apoptotic damage to the hippocampus and homocysteine (Hcy) accumulation to neurotoxic levels in the cerebrospinal fluid of children. The Hcy pathway controls bioavailability of methyl and its homeostasis can be modulated by vitamin B12, cofactor of the methionine synthase enzyme. Herein, the neuroprotective potential and the underlying mode of action of vitamin B12 adjuvant therapy were assessed in an infant rat model of BM.MethodsEleven-day old rats were intracysternally infected with Streptococcus pneumoniae serotype 3, or saline, treated with B12 or placebo, and, 24h after infection, their hippocampi were analyzed for apoptosis in the dentate gyrus, sulfur amino acids content, global DNA methylation, transcription and proximal promoter methylation of candidate genes. Differences between groups were compared using 2-way ANOVA 2-way followed by Bonferroni post-hoc test. Correlations were tested with Spearman’s test.ResultsB12 attenuated BM-induced hippocampal apoptosis in a Hcy dependent manner (r = 0.80, P < 0.05). BM caused global DNA hypomethylation, however B12 restored this parameter. Accordingly, B12 increased the methylation capacity of hippocampal cells from infected animals, as inferred from the ratio S-adenosyl methionine (SAM):S-adenosyl homocysteine (SAH) in infected animals. BM upregulated selected pro-inflammatory genes, and this effect was counteracted by B12, which also increased methylation of CpGs at the promoter of Ccl3 of infected animals.ConclusionHcy is likely to play a central role in hippocampal damage in the infant rat model of BM, and B12 shows an anti-inflammatory and neuroprotective action through methyl-dependent epigenetic mechanisms.